Reagents For Oxidizer-Based Chemical Detection

ABSTRACT

Reagents and methods are disclosed for detection of oxidizers and inorganic salts and other analytes of interest. The reagents can interact with their target analytes, especially oxidizer compositions or oxidizer-based explosives, to selectively enhance their ionization yield, interacting by chemical reaction or by forming an associative adduct which facilitates their detection. For example, the reagents can adduct with the counter-ion of the intended analyte for improved direct detection and/or react chemically via acid-base reactions to produce a new product for detection. In another aspect of the invention, reactive reagents and methods are also disclosed that facilitate indirect detection of the analyte at lower temperatures based on reduction-oxidation (redox) chemistry. These reagents are particularly useful in detecting oxidizer analytes.

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S.Provisional Patent Application No. 61/674,980 filed Jul. 24, 2012 andU.S. Provisional Patent Application No. 61/806,636, filed Mar. 29, 2013.

This application is also a continuation-in-part of U.S. patentapplication No. 13/832,905 filed Mar. 15, 2013.

The contents of each of the above-referenced related application areherein incorporated by reference in its entirety.

GOVERNMENT RIGHTS

This invention was made with U.S. government support under InteragencyAgreements HSHQDC-09-X-00439 and HSHQPM-12-X-00057 by the U.S.Department of Homeland Security, Science and Technology Directorate, andperformed by MIT Lincoln Laboratory under Air Force Contract No.FA8721-05-C-0002. The U.S. government has certain rights in theinvention.

FIELD OF THE INVENTION

The present invention concerns contraband detection and, in particular,novel reagents for spectrometric detection of oxidizer-based explosivesin ambient pressure ionization detectors and the like.

BACKGROUND OF THE INVENTION

The evolving threats posed by concealed explosives or the intentionalrelease of toxic chemicals demand new ways to detect these threats andprotect the public. Typically, the techniques for identifying threatmolecules involve ionizing a sample and then detecting whether thethreat molecule (analyte) is present. The detection mechanisms includeion mobility spectrometry (IMS), differential mobility spectrometry(DMS), field asymmetric ion mobility spectrometry (FAIMS) and massspectrometry (MS), all of which rely upon ionization of the analyte or acomplex that includes the analyte. In fact, one of these techniques(IMS) is currently used in nearly every airport in the United States asa means to prevent concealed explosives from getting on aircraft.

Given the importance of these techniques to public safety, considerableeffort has been devoted to develop better techniques for efficiently(and selectively) ionizing analytes in order to provide the greatestdetection capability.

In almost all instances, ionization is achieved selectively byperforming the ionization under ambient-pressure conditions in thepresence of an ionization reagent in a technique known asambient-pressure ionization (API) (also sometimes calledatmospheric-pressure chemical ionization). In API, the target analyte isdrawn into a space containing both an ionization source and anionization reagent, and ionization of the target molecule takes placethrough ion-molecule collisions. The ionization reagent is selected suchthat rapid achievement of charge equilibrium results in charge or protontransfer from the reagent to the target molecule.

Since many explosive and chemical threats have low vapor pressure andexist as traces of particulates or thin films on surfaces, the mostcommon way to collect a sample requires a swipe or swab substrate whichprovides a physical mechanism to both collect and preconcentrate asample taken from a surface of a suspect object for subsequentpresentation to the ionization space of the detection instrument. Thesubstrate media, which is called a “swipe,” can be thermally heated todesorb the target analyte into the vapor phase for subsequent ionizationand detection. This methodology is currently used in fielded IMS systemsthat detect explosives, where detection relies on efficient collectionand presentation of low-vapor analytes such as 2,4,6-trinitrotoluence(TNT), 1,3,5-trinitro-1,3,5-triazacyclohexane (RDX) and pentaerythritoltetranitrate (PETN) into the instrument, and use of ionization reagentsthat enhance the formation of negative ions via chloride adduction, suchas methylene chloride.

In such explosive detection systems, the swipe or substrate is typicallypositioned in a thermal desorber located on the inlet side of thedetection system. Thermal heating of the solid particles on the swipeinduces a solid-to-vapor phase transition and releases the analytemolecules as a vapor, usually guided into the sensor inlet by a carriergas, and the ionization reagent is introduced as a vapor within aseparate carrier gas. Properties of commercially-available swipe mediahave been optimized over the years for increased efficiency of particlecollection from surfaces (mechanical or electrostatic), efficienttransfer and release of analyte into the chemical sensor, thermalstability, and low chemical background of the substrate.

Detection of both inorganic and organic oxidizer-based explosives can bea particularly difficult problem. Some examples of inorganicoxidizer-based explosives include perchlorate (KClO₄, NaClO₄), chlorate(KClO₃, NaClO₃), and nitrate (NH₄NO₃, KNO₃, NaNO₃) salts and hydrogenperoxide (H₂O₂). Examples of organic oxidizer-based explosives arehexamethylene triperoxide diamine (HMTD), triacetonetriperoxide (TATP),and diacetonediperoxide (DADP). inorganic oxidizers, generally speaking,are chemical compositions that contribute oxygen in which the fuelcomponent of an explosive can burn. Two factors that contribute to thedifficulty in detecting inorganic oxidizers are their low vapor pressureand low ionization yield. Low volatility analytes require high thermaldesorption and/or ionization source temperatures. (In some cases thetemperature necessary to transform oxidizer analytes into their vaporphase can exceed 350° C.—a regime in which common swipe materials cannotbe used.) Achieving high temperature is an engineering challengespecifically in smaller, field portable systems where size, weight andpower must be minimized and long thermal cycling reduces samplethroughput. Even when ionized, this class of analytes are often prone toquickly recombine into neutral species before they can be subjected tospectrometric analysis. Moreover, some of the analytes also formubiquitous, non-specific products upon thermal desorption, e.g. nitratefrom ammonium nitrate, potassium nitrate, and sodium nitrate.

Accordingly, there exists a need for better methods and reagents fordetecting oxidizer compositions and oxidizer-based explosives. Reagentsthat can improve desorption (release of analytes from a substrate),increase the quantity or longevity of ionized analyte species orotherwise improve the detector efficiency would satisfy a long-feel needin the field. Additionally, indirect techniques for detecting orquantifying oxidizer analytes based on formation of complexes orchemical modification of reagents, which can be more readily detected,would also provide an improvement in the art.

SUMMARY Of THE INVENTION

Reagents and methods are disclosed for detection of both inorganic andorganic oxidizers, inorganic salts and other analytes of interest. Thereagents can interact with their target analytes, especially oxidizercompositions or oxidizer-based explosives, to selectively enhance theirionization yield, interacting by chemical reaction or by forming anassociative adduct which facilitates their detection. For example, thereagents can adduct with the counter-ion of the intended analyte forimproved direct detection of the analyte and/or react chemically viaacid-base reactions to produce a new product for detection. Reactivereagents and methods are also disclosed that facilitate indirectdetection of the analyte at lower temperatures based onreduction-oxidation (redox) chemistry. These reagents are particularlyuseful in detecting oxidizer analytes, such as salts of nitrates,nitrites, chlorates, perchlorates, permanganates, dichromates or osmiumtetraoxide.

In one aspect of the invention, associative reagents are disclosed toimprove ionization yield. In some instances, the reagents can alsoimprove yield at lower temperatures than currently necessary to achievea desired degree of accuracy. In certain embodiments, the reagents serveto sequester one or more ionic species. For example, detection ofcertain oxidizers, such as potassium perchlorate KClO₄, is limited inconventional ambient pressure ionization systems by the ionizationyield. Associative reagents are disclosed that can sequestor the cation(e.g. K⁺) from the intended analyte (e.g. ClO₄ ⁻ in negative modeionization) which will increase the availability of the analyte(perchlorate) for direct detection. This premise will also functionwhere a reagent binds the anion leaving the cationic analyte free to bedirectly detected. In either case, if needed for improving detection, aco-reagent molecule may also be used to adduct to or react with theanalyte ion produced in the first interaction.

In another aspect of the invention, evaporative reagents are disclosedto increase the vapor pressure of the analyte or a component thereof.For example, the evaporative reagent can serve as a proton donor andshift the equilibrium in favor of forming the acid of the salt. The acidanalog can enhance direct detection of the analyte by increasing vaporpressure and/or improving ionization probability at lower temperatures.The volatile protonated analyte can then be readily ionized fordetection. This acid-base equilibrium approach can be exploded as asingle reagent system or in tandem with an associative reagent, asneeded to enhance detection.

Thus, in yet another aspect of the invention, a two (or multi) reagentsystem is disclosed combining an evaporative reactant (e.g., a H⁺ donorto form an acidic analog of the analyte) with a counter-ion associativereagent. The associative reagent will ensure that, followingvolatilization and ionization, the analyte will not quickly recombinewith its counter ion into a neutral species.

In another aspect of the invention, reactive reagents are disclosed thatfacilitate indirect detection of the analyte at lower temperatures basedon reduction-oxidation (redox) chemistry. These reagents areparticularly useful in detecting oxidizer analytes. In one embodiment,the redox reagents accept one or more oxygen atoms from oxidizerspresent in the sample. The oxidized reagent species can then be detectedby mass spectrometry and the amount of oxidized reagent detectedprovides an indirect indication of the presence of an oxidizer in asample.

The invention can also be used in conjunction with other ionizationreagents, such as conventional compositions currently used inspectrometric detection that enhance the ionization of desorbedmolecules that are volatized from a sample (or a swipe carrying asample). Ionization reagents useful in the present invention include,for example, polychlorinated alkanes, alkyl amines, and nicotinamide.

The invention can be practiced in various detection systems and isparticularly useful in ambient pressure ionization detectors. In suchsystems, the substrate is positioned in a thermal desorber located onthe inlet side of the detection system. Thermal heating of the solidparticles on the swipe induces a solid-to-vapor phase transition andreleases the analyte molecules as a vapor, usually guided into thesensor inlet by a carrier gas, and the ionization reagent is introducedas a vapor within a separate carrier gas. Properties ofcommercially-available swipe media have been optimized over the yearsfor increased efficiency of particle collection from surfaces(mechanical or electrostatic), efficient transfer and release of analyteinto the chemical sensor, thermal stability, and low chemical backgroundof the substrate. Prior art exists in the patent literature on differentembodiments of sampling swipes (e.g., Smiths Detection, Sampling Swabrelated patents: US20060192098A1; EP1844189A2; WO2007066240A3). In aprevious U.S. patent application No. 61/674,980 entitled “ReagentImpregnated Swipe for Thermal Desorption Release and Chemical Detectionwith Ambient Ionization Techniques”, we disclosed an invention where thereagent is chemically embedded in the swipe material for interactionwith the analyte.

The reagents of the present invention can be introduced in any physicalstate including the gas-phase from a vapor permeation device, as a solidon/in a swipe or other substrate, as a liquid infused via nebulizer, orby other various methods for introduction known to those skilled in theart.

In certain embodiments, the reagents of the present invention are lowvolatility compounds. For example, the reagents can have vapor pressuresless than 1 or 10⁻¹ or 10⁻² or 10⁻³ Torr.

In certain embodiments, the associative reagent is adapted to form ahost-guest complex with the analyte or its counter-ion constituent. Theassociative reagent can include at least one of β-keto esters, crownethers, glymes, sugars, cryptands, ionic dyes, and cavitands.

In yet another aspect of the invention, the reagents, of the presentinvention can be impregnated or otherwise pre-associated with a swipe orother substrate used to collect a sample for analysis. The swipes canfurther include a plurality of reagents. The plurality of reagents canbe associated with spatially separated portions of the swipe or theplurality of reagents can be uniformly applied to substrate. In certainembodiments, the plurality of reagents having different vaporizationtemperatures. In other embodiments, the swipe can also include one ormore internal standards.

The substrate component of the swipe can be formed from variousmaterials, including least one of paper, fabric, cloth, fibrous matte,gauze, cellulose, cotton, flax, linen, synthetic fibers and blends ofsuch materials. The substrate should be clean, and free of extractables,such dirt, grime, contaminants, incidental materials or fabricationresidues. In certain preferred embodiments, the substrate has anextractables content of less than 3% or 2% or 1% or 0.1% or 0.01 %during desorption. The substrate is preferably also capable of resistingdecomposition at temperatures up to about 300° C.

In another aspect of the invention, methods of detecting a targetanalyte are disclosed, which can include the steps of ionizing moleculespresent in a sample; exposing the sample molecules to ionizationreagents and/or associative reagents, evaporative reagents or redoxreagents and analyzing the ionized molecules to detect the targetanalyte. The methods can further include forming at least one chargedcomplex of the reagent and a target analyte or its counter-ion; andanalyzing at least one of the resulting charged species to detect atarget analyte. The methods can further include exposing aproton-donating reagent to the sample molecules to modify the vaporpressure, rate of vaporization or ionization potential of the samplemolecules.

The step of analyzing the ionized material can further include detectionof the charged analyte, charged complex or reactive product by ionmobility spectrometry, differential mobility spectrometry, fieldasymmetric spectrometry or mass spectrometry. In one preferredembodiment, the ionized molecules are detected by ion mobilityspectrometry. Alternatively, they can be detected by mass spectrometry.

By co-introducing and vaporizing both the target analyte and the reagentinto the ionization space of an instrument, the two become incommunication with one another resulting in ionization of the analytefor direct detection or an oxidized product for indirect detection. Theionization can result in increased ion yield or form a new chemicalproduct with unique characteristics for detection. Also, if the analytemolecule itself was previously undetectable, use of an associativebinding reagent for the counter-ion causing its removal from the analyteion and/or the formation of the more volatile analog of the analyte canallow detection.

When a reagent of the present invention is incorporated into a swipe,the methods of the present invention can further include employing theswipe to collect a sample, heating the swipe to vaporize the moleculespresent on the swipe and ionizing the molecules, preferably in somecases under ambient pressure conditions. In certain embodiments, thereagent can be a low volatility compound. The methods can furtherinclude employing swipes that include multiple reagents. For example,the swipe can include multiple reagents associated with spatiallyseparated portions of the swipe and the step of ionization can furtherinclude heating different portions of the swipe in sequence.

Alternatively, two or more reagents having different vapor pressures canbe applied to the substrate and the step of ionizing can further includeexposing the swipe to a thermal gradient such that the reagents arereleased sequentially.

More generally, the invention allows the use of reagents for adductformation and/or chemical reaction to provide flexibility in detecting awider range of analytes (or for more selective detection) in sampleswith current and future API-based technologies. Also, a series ofreagents ma be utilized by introduction simultaneously or at discretetimes and temperatures to induce selective reactions with expectedoxidizers (e.g. reagent A for perchlorate, reagent B for chlorate,reagent C for hydrogen peroxide, reagent D for TATP, reagent E forHMTD).

BRIEF DESCRIPTION OF THE DRAWINGS

The appended drawings have been included herein so that theabove-recited features, advantages and objects of the invention willbecome clear and can be understood in detail. These drawings form a partof the specification. It is to be noted, however, that the appendeddrawings illustrate preferred embodiments of the invention and shouldnot be considered to limit the scope of the invention.

FIG. 1 illustrates three schema for employing associative and/oracid-base reactive reagents for direct detection of an oxidizer orinorganic salt MX;

FIG. 2 is a single quadrupole negative-mode mass spectra showingreduction to practice for use of an associative reagent (dibenzo21-crown-7) to preferentially sequester the potassium counter-ion ofpotassium perchlorate to increase the available perchlorate anion (m/z99 for ClO₄ ⁻ and m/z 101 for ClO₄ ⁻) for ionization. The detectionsensitivity increased by a factor of 10 using the associative reagent.

FIG. 3 is a flowchart of the TD-APCI method, including solid samplepreparation, that was used to demonstrate the present invention. Theprocess shown in FIG. 3 was used to demonstrate that the molar ratiobetween the reagent and the analyte determines the reaction efficiency,and by extension, the efficacy of the present invention. In cases wherethere is an excess of analyte (explosive), there is insufficientquantity of the reagent to react with all the explosive and the benefitsof the present invention are limited. This circumstance is considered“reagent limited”. In order to ensure maximum reaction of the analyte(explosive) with the reagent, an excess of reagent is needed. In thiscircumstance the reaction is considered “explosive limited”. Thepreferred embodiment of this invention is to operate in the “explosivelimited” regime, although some benefit is also realized in the “reagentlimited” regime as well. The example shown in FIG. 3 is for potassiumperchlorate and dibenzo-21-crown-7 (DB21C7) reagent generating highlyvolatile HClO₄ for detection of the ClO₄ ⁻ anion.

FIG. 4 is a flowchart of the TD-APCI method including solid samplepreparation in which the molar ratio of the dropcast sample can beeither “reagent-limited” or “explosive-limited”. The signal enhancementis dependent on the molar ratio between the reagent and the explosive.The example shown in FIG. 4 is for potassium perchlorate anddibenzo-21-crown-7 (DB21C7) reagent generating highly volatile HClO₄ fordetection of the ClO₄ ⁻ anion.

FIG. 5 is a graph of TD-APCI of potassium perchlorate (KClO₄) where theinstrument response (peak area) is plotted as a function of thermaldesorption APCI source temperature (triplicate measurements) for 5 μgKClO₄ (diamonds), 5 μg KClO₄ with 10 μg dibenzo-21-crown-7 (DB21C7)(squares), and background (clean silicon wafer substrate, triangles;

FIG. 6 is a graph showing TD-APCI-MS/MS instrument response vs thermaldesorption temperature for potassium perchlorate (KClO₄) with andwithout dibenzo-21-crown-7 (DB21C7) reagent rendered asbackground-subtracted signal intensity determined using data in FIG. 5,comparing 5 μg KClO₄ (diamonds) and 5 μg KClO₄ with 10 μgdibenzo-21-crown-7 (DB21C7) (squares), where background is a cleansilicon wafer substrate.

FIG. 7 is a graph showing TD-APCI-MS/MS instrument response vs thermaldesorption temperature for potassium perchlorate (KClO₄) with andwithout dibenzo-21-crown-7 (DB21C7) reagent rendered assignal-to-background ratio determined using data in FIG. 5, comparing 5μg KClO₄ (diamonds) and 5 μg KClO₄ with 10 μg dibenzo-21-crown-7(DB21C7) (squares), where background is a clean silicon wafer substrate;

FIG. 8 is a graph of TD-APCI of sodium perchlorate (NaClO₄) where theinstrument response (peak area) is plotted as a function of thermaldesorption APCI source temperature (triplicate measurements) for 5 μgNaClO₄ (diamonds), 5 μg NaClO₄ with 10 μg dibenzo-21-crown-7 (DB21C7)(squares), and background (clean silicon wafer substrate, triangles);

FIG. 9 shows TD-APCI-MS/MS instrument response vs thermal desorptiontemperature for sodium perchlorate (NaClO₄) with and withoutdibenzo-21-crown-7 (DB21C7) reagent rendered as background-subtractedsignal intensity determined using data in FIG. 8, comparing 5 μg NaClO₄(diamonds) and 5 μg NaClO₄ with 10 μg dibenzo-21-crown-7 (DB21C7)(squares), where background is a clean silicon wafer substrate;

FIG. 10 shows TD-APCI-MS/MS instrument response vs thermal desorptiontemperature for sodium perchlorate (NaClO₄) with and withoutdibenzo-21-crown-7 (DB21C7) reagent rendered as signal-to-backgroundratio determined using data in FIG. 8, comparing 5 μg NaClO₄ (diamonds)and 5 μg NaClO₄ with 10 μg dibenzo-21-crown-7 (DB21C7) (squares), wherebackground is a clean silicon wafer substrate;

FIG. 11 illustrates the concept of doping a chemical reagent intosubstrate media (usually a fabric of polyester, muslin, or cotton)entraining low volatility compounds until released by desorption (e.g.thermal) and provides a flow diagram comparing a reagent impregnatedswipe approach (bottom flow diagram) versus the use of swipes with nochemical modification (top flow diagram);

FIG. 12 is an overlay of two positive-mode mass spectra showing lack ofdetection of ammonium nitrate residue thermally-desorbed from anon-impregnated swipe (lower line) and detection of ammonium nitrateresidue thermally-desorbed from the polyester swipe impregnated withdibenzo-21-crown-7 reagent M (upper line);

FIG. 13 illustrates general classes of reducing agents for use in theindirect detection of analytes that are strong oxidizers. FIG. 13illustrates reactive reducing reagent chemistries including redoxreactions between classes of carbon, phosphorous sulfur and nitrogenbased compounds and oxidizers. Here, one or more new products aregenerated for indirect detection of the oxidizing analyte. In thesestructures, R1, R2 and R3 can be alkyls, lower alkyls, substitutedalkyls, substituted lower alkyls, aryls, or substituted aryls such thattheir vapor pressures are at least 0.001 Torr at 25° C.

FIG. 14 is a negative mode APCI MS Q1 scan for 4-nitrophenylboronic acidin 50/50 methanol-water (solid) and 4-nitrophenylboronic acid withhydrogen peroxide in 50/50 methanol-water (crossed); and

FIG. 15 illustrates the signal-to-background ratio calculated forindirect detection of hydrogen peroxide in negative mode MS/MS by thesignal decrease of 4-nitrophenylboronic acid monitored by m/z 166→46(C₆H₅BNO₄ ⁻ to NO₂ ⁻) and the signal increase of 4-nitrophenol monitoredby m/z 138→92 (C₆H₄NO₃ ⁻ to C₆H₄O⁻) plotted as a function of hydrogenperoxide concentration.

DETAILED DESCRIPTION OF THE INVENTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment can be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural references unless the contentclearly dictates otherwise. The terms used in this invention adhere tostandard definitions generally accepted by those having ordinary skillin the art. In case any further explanation might be needed, some termshave been further elucidated below.

The term “about,” as used herein, refers to variations in a numericalquantity that can occur, for example, through measuring or handlingprocedures in the real world; through inadvertent error in theseprocedures; through differences in the manufacture, source, or purity ofcompositions or reagents; and the like. Typically, the term “about” asused herein means greater or lesser than the value or range of valuesstated by 1/10 of the stated values, e.g., ±10%. For instance, aconcentration value of about 30% can mean a concentration between 27%and 33%. The term “about” also refers to variations that would berecognized by one skilled in the art as being equivalent so long as suchvariations do not encompass known values practiced by the prior art.Each value or range of values preceded by the term “about” is alsointended to encompass the embodiment of the stated absolute value orrange of values. Whether or not modified by the term “about,”quantitative values recited in the claims include equivalents to therecited values, e.g., variations in the numerical quantity of suchvalues that can occur, but would be recognized to be equivalents by aperson skilled in the art.

Mass spectrometry is an analytical process for identifying a compound orcompounds in a sample by assessing the molecular weight, chemicalcomposition and structural information based on the mass-to-charge ratioof charged particles. Mass spectrometry is widely considered to have thebest specificity of any technique applicable to a broad class ofexplosive compounds. In general, a sample undergoes ionization to formcharged particles as ions; these charged particles are then passedthrough electric and/or magnetic fields to separate them according totheir mass-to-charge ratio. The terms “mass spectrometry” and“spectrometry” are used herein to encompass techniques that produce aspectrum or spectra of the masses of molecules present in a sample. Massspectrometry includes, but is not limited to, ion mobility spectrometry(IMS), differential mobility spectrometry (DMS), field asymmetric ionmobility spectrometry (FAIMS), and mass spectrometry (MS), all of whichrely upon ionization of the analyte or a complex that includes theanalyte. The analysis performed in spectrometry is typically referred toas “mass/charge” analysis, a method of characterizing the ions detectedby a a spectrometer in terms of their mass-to-charge ratio. Theabbreviation m/z is used to denote the dimensionless quantity formed bydividing the mass number of an ion by its charge number. It has longbeen called the mass-to-charge ratio although m is not the ionic massnor is z a multiple or the elementary (electronic) charge, e. Thus, forexample, for the ion C₇H₇ ²⁺, m/z equals 45.5.

The ionization process can be performed by a wide variety of techniques,depending on the phase (solid, liquid, gas) of the sample and theefficiency of the target analyte(s) in question. Some examples of ionsources can include electron ionization, glow discharge ionization,resonant ionization, field desorption, fast atom bombardment,thermospray, desorption/ionization on silicon, atmospheric pressurechemical ionization, spark ionization, inductively coupled plasmaionization, secondary ionization by sputtering ion beams off thetarget's surface, and thermal ionization.

Ambient-pressure ionization, collision-induced ionization, andatmospheric-pressure chemical ionization refer to a characterizationtechniques in which picogram to microgram quantities of an analyte canbe analyzed. The process generally refers to a chemical sample that isintroduced into an ionization region as either a solid, liquid, or gas.In the ionization region, the analyte is in contact with other gases andions that are part of the ionization region. Additional ions areproduced through the collision of the analyte molecules with ions withinthe ionization reagent that are present in the ion source,electro-magnetic device. Inside the ion source, the ionization reagentis present in large excess compared to the analyte. Electrons and/orions entering the source will preferentially ionize the ionizationreagent. Collisions with other ionization reagent molecules will inducefurther ionization, creating positive and/or negative ions of theanalyte. The ions are drawn into the spectrometer by either a carriergas or focused into a beam by an electromagnet, then separated intoindividual beams based on the mass/charge ratio of the ions. The ionbeams are separated in a mass spectrometer and collected eithersequentially in a single detector or simultaneously in a set of multipledetectors to yield isotopic ratios. Highly accurate results require thatsample cross-contamination be minimized.

The traditional methods for explosives detection usually involve wipingthe ambient surface with a special material wipe followed by thermaldesorption/gas phase ionization of the explosive compounds in thepresence of an ionization reagent. However, this method is not ideal forthe detection of thermally labile explosives or explosives which havelow vapor pressures. Low-volatility explosives are those which releasevery small amounts of the explosive vapor, typically at parts pertrillion levels or lower, even when heated, making it extremelydifficult to detect.

The terms “desorption,” “desorb” and “desorbing” as used herein refer totechnology of increasing the volatility of molecules, for example targetanalytes, such that they can be removed (separated) from the solid.Thermal desorption is not incineration, but uses heat and a flow ofinert gas to extract volatile and semi-volatile organics retained in asample matrix or on a sorbent bed. The volatilized compounds are theneither collected or thermally destroyed.

In certain embodiments, the reagents of the present invention are lowvolatility compounds. The terms “low volatility” and “low vaporpressure” as used herein are intended to describe compositions that donot readily evaporate or sublimate at room temperature (e.g., at about25° C. Typically such low volatility compositions are solids or viscousliquids and have a vapor pressure at room temperature of less than 1Torr, or more typically less that 10⁻¹ Torr. In some preferredembodiments, the low volatility reagents of the present invention canhave a vapor pressure at room temperature of or less that 10⁻² Torr or,more preferably, less that 10⁻³ Torr.

One new class of new ionization reagents, referred to herein as“associative reagents,” can include a crown ether, a glyme, a sugar, acryptand, or a cavitand. These compounds can be used as reagents and canform host-guest complexes with target analytes. These reagents include,but are not limited to, crown ethers (such as 12-crown-4, 15-crown-5,16-crown-4, dibenzo 21-crown-7 or 18-crown-6), glymes (such asdimethoxyethane), sugars (such as sucrose, fructose, glucose), cryptands(such as 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8] hexacosane,kryptofix 222), and cavitands (such as cyclodextrin, calixarene,pillararene and cucurbituril). These compounds can be applied to thesubstrate material by a chemical process which can include immersion ina concentrated solution, liquid spray application, or vapor deposition.Alternatively, low volatility associative reagents can be introduced viaa chemically doped swipe material.

“Crown ethers” are cyclic chemical compounds that consist of a ringcontaining several ether groups, e.g., oligomers of ethylene oxide orderivatives of catechol. “Glymes” are derivatives of glycol ethers,e.g., dimethyloxyethanes, and include, monoglymes, diglymes, ethylglymesand tetraglymes. “Cryptands” are bi- and polycyclic multidentatecompounds capable of encapsulating various cations. “Cavitands” are alsocontainer shaped molecules having cavities to engage in host-guestchemistry with guest molecules of a complementary shape and size.

Additionally, the ionization reagents of the present invention can forma host-guest complex with a target analyte. The term “host-guest”complex as used herein generally refers to complexes that are composedof two or more molecules or ions that are held in a structuralrelationship, at least in part, by noncovalent bonding. The host-guestcomplex can be held together in unique structural relationships byforces other than those of full covalent bonds. Host-guest chemistryencompasses molecular recognition and interactions throughthree-dimensional structures of the molecules to transiently bind one toanother. The noncovalent interaction between the ionization reagent andthe target analyte can be any type of, for example, hydrogen bonding,ionic bonding, van der Waals forces and hydrophobic interactions.

The terms “alkyl” or “alkyl group” means a linear or branched C₁₋₁₂alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl or octyl. A“lower alkyl” group means a linear or branched C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, pentyl and isopentyl. The alkyl or lower alkyl group may beoptionally substituted with one or more groups selected from among ahalogen atom, a cyano group, a hydroxyl group, a carboxyl group, anamino group, an acyl group, a sulfo group, a phosphoryl group, a cyclicamino group, an aryl group, and an alkoxy group.

The products of the reagents of the present invention and their analytescan be formed during desorption or on the surface of, or within a swipematerial, e.g., by interactions between the analyte and the reagentprior to desorption or ionization. The swipe, also referred to as asmear, wipe or substrate material, can be made of paper, metal, fabric,cloth, fibers, glass, or synthetic material. In one embodiment, theswipe is a fabric of polyester, muslin, or cotton. The swipe can also bein different shapes and sizes depending on the type of surface to besampled. For example, the swipe can be a two-dimensional material. Thetwo-dimensional material can be sheet-like in construction. The materialcan also be in a multitude of sizes and shapes. In another example, theswipe can be a swab or other three-dimensional swipe.

The swipe can be formed of material that can be resistant to chemicaldegradation during testing in the approximate pH range of 0.1 through 14to avoid reacting or decomposing. The swipe can be white in color to aidtest evaluation, can be heat resistant, absorbent and/or chemicallyresistant at elevated temperatures and can have hydrophilic propertiesfor wetting when using fluid reagents. The swipe can also be roughened,for example, by use of a woven material, to aid in retrieving testsample particles from the environment. The swipe can also be thickenough to resist damage such as tearing during sampling, yet not be toothick such that heating of the test sample is inhibited. The swipethickness can be optimized to achieve rapid, and even heating throughthe material layer.

The swipe, such as the swab, can be affixed to the end of a holder. Theswipe can be permanently or temporarily affixed to the holder for easeof manipulation, usage and sampling. The swipe can also be for a singleuse, such as being disposable. In an exemplary embodiment, the surfaceof the swipe is clean, sterile, or uncontaminated with target analytes.The swipes can also be dry, damp or wet prior to use. When the swipesare used in a damp or wet state, the swipes can be dampened with asolution, such as distilled water, alcohol, or a working strength of amultipurpose detergent.

The swipes can also sample a dry, damp or wet surface. The swipes can beof absorbent material to collect the damp or wet samples. The samplesurface can also be prepped by wetting or dampening with a solutionprior to sampling with the swipe. The surface can be dampened with asolution, such as distilled water, alcohol, or a working strength of amultipurpose detergent.

One or more reagents according to the invention can be deposited on,embedded in or otherwise associated with, the swipe to detect one ormore target analytes. The reagent association with the swipe can bethrough physical entrainment, non-covalent bonds, or thermally labilecovalent bonds. When multiple reagents are employed, each reagent canallow the detection of a unique target analyte. The individual targetanalytes can be analyzed on the swipe at predetermined times and/ortemperatures or temperature ranges. Each reagent deposited on, embeddedin or in association with the swipe can react to a specific targetanalyte.

The swipe can be substantially adapted to receive or present one or morereagents to detect one or more target analytes. The swipe can have aplurality of test regions, quadrants or lines. A different ionizationreagent can be deposited on each test region, quadrant or line or theswipe, generating a unique detection area of the swipe. The entire swipecan collectively generate a unique pattern or code for a particulartarget analyte or class of target analytes. The test regions, quadrantsor lines can be detected separately or at the same time to generate theunique pattern or code for the particular target analytes or class oftarget analytes.

FIG. 1 provides three schema for employing associative and/orevaporative (e.g., acid-base reactive) reagents for direct detection ofan oxidizer or inorganic salt MX where an associative reagent (Scheme 1)preferentially binds the counter-ion X⁺ of the analyte to increaseavailability for detection of M⁻ in negative ionization mode, where anevaporative reagent (Scheme 2) donates a proton to the analyte formingthe acid form HM as a more volatile product for ionization anddetection, or a co-reagent (Scheme 3) incorporating both an associative,A or R, and a reactive reagent, H, if needed, to form a more readilydetected analyte product.

In scheme 1 of FIG. 1, dissociation of the neutral parent compound tothe anionic analyte increases the abundance of ionized analyte and,therefore, increased detection sensitivity. Compounds which can be usedas associative reagents can form host-guest complexes with thecounter-ion of the desired analyte(s) and may include but are notlimited to crown ethers, glymes, sugars (sucrose, fructose, glucose),cryptands, and cavitands. Specifically, this reagent list includes18-crown-6, dibenzo-21-crown-7, 15-crown-5, 12-crown-4,methylacetoacetate, acetophenone, acetylacetone, triglyme, tetraglyme,sucrose, fructose, glucose, kryptofix 222 and 4-tert-butylcalix[6]arene.

In scheme 2, formation of the acid analog of the analyte provides a newchemical product with higher vapor pressure, therefore increasedavailability at lower desorption temperatures, e.g. perchloric acid (7Torr at room temperature) from potassium perchlorate (vapor pressuremuch less than 10⁻⁶ Torr, melting point 356° C.).

More generally, the evaporative reagents of the present invention canreact with an ionic analyte by forming a conjugate that is more volatilethan the target analyte species itself, e.g., by forming the conjugateacid of the analyte through an acid-base reaction, thereby increasingthe vapor pressure of the analyte species and allowing the anion to bemore readily available for detection in an ion detection apparatus.

In certain embodiments, the reagent compound is an acid (proton donor)which may include but is not limited water, sulfuric acid, hydrochloricacid, hydrofluoric acid, hydroiodic acid, hydrobromic acid, nitric acid,oxalic acid, hydrogen sulfate, phosphoric acid, formic acid, benzoicacid, acetic acid, propionic acid, or other organic acids of the formR—COOH where R is an alkyl, substituted alkyl, aryl, or substituted arylgroup. Use of the acid reagent results in the formation of one or moreions for detection by interaction between the reagent and analyte(s).

Various other compositions can also serve as evaporative reagents, solong as they are capable of converting an analyte (or an ionic speciesof an analyte) into a composition having a higher vapor pressure thanthe analyte itself. For example, quaternary ammonium compounds, such astetraalkylammonium hydroxide (NR₄OH), can serve as an evaporative agentsfor detection of nitrates, such as KNO₃, by forming more volativenitrate species, e.g., NR₄ No₃. The class of evaporative reagents caninclude alkylammonium salts, hydroxides, etc. that generate alkylammonium cations (N-R1-R2-R3-R4 where R1-R4 are preferably the same ordifferent, straight or branched, lower alkyls).

With reference again to FIG 1, scheme 3 illustrates that, for certainanalytes, a co-reagent system employing both an associative reagent forthe counter-ion and an evaporative reagent to donate a proton (or othercation) to the analyte in an acid-base reaction can be useful toincrease detection.

EXAMPLE 1

This invention, has been reduced to practice and employed to detectpotassium perchlorate via API mass spectrometry. As described earlier,in negative-mode atmospheric pressure chemical ionization, theionization efficiency is extremely limited. In order to increase theamount of free perchlorate anion available for detection, an associativereagent was added. In these experiments, a solid reagent, namelydibenzo-21-crown-7 (CAS#14098-41-0), was added to the sample solutioncontaining potassium perchlorate at equimolar concentrations inmethanol. The perchlorate anion (³⁵ClO₄ ⁻) is present at m/z 99. Weinfused this solution into the APCI TurboV ionization source of a4000QTrap MS (ABSCIEX) operating in negative polarity and detected theionized perchlorate anion, ClO₄ ⁻.

FIG. 2 is a single quadrupole negative mode mass spectra showing the useof an associative reagent (dibenzo 21-crown-7) to preferentiallysequester the potassium counter-ion of potassium perchlorate to increasethe available perchlorate anion (m/z 99 for ³⁵ClO₄ ⁻ and m/z 101 for³⁷ClO₄ ⁻) for ionization. The detection sensitivity increased by afactor of 10 using the associative reagent.

EXAMPLE 2

FIG. 3 is a flowchart of the TD-APCI method, including solid samplepreparation, that was used to demonstrate the present invention. Theprocess shown in FIG. 3 was used to demonstrate that the molar ratiobetween the reagent and the analyte determines the reaction efficiency,and by extension, the efficacy of the present invention. In cases wherethere is an excess of analyte (explosive), there is insufficientquantity of the reagent to react with all the explosive and the benefitsof the present invention are limited. This circumstance is considered“reagent limited”. In order to ensure maximum reaction of the analyte(explosive) with the reagent, an excess of reagent is needed. In thiscircumstance the reaction is considered “explosive limited”. Thepreferred embodiment of this invention is to operate in the “explosivelimited” regime, although some benefit is also realized in the “reagentlimited” regime as well. The example shown in FIG. 3 is for potassiumperchlorate and dibenzo-21-crown-7 (DB21C7) reagent generating highlyvolatile HClO₄ for detection of the ClO₄ anion.

FIG. 4 shows results demonstrating that DB21C7 increases thesignal-to-background ratio by a factor of greater the 25—for detectionof ClO₄ ⁻ from KClO₄ when the reagent is present in molar excess overthe explosive.

FIG. 5 is a graph of TD-APCI of potassium perchlorate (KlCO₄) where theinstrument response (peak area) is plotted as a function of thermaldescription APCI source temperature (triplicate measurements) for 5 μgKClO₄ (diamonds), 5 μg KClO₄ with 10 μg dibenzo-21-crown-7 (DB21C7)(squares), and background (clean silicon wafer substrate, triangles).This data shows the temperature effect on instrument response (reportedas signal-to-background ratio) while the mass loading of the explosiveand reagent remained a constant 1:2 ratio using 5 μg explosive with 10μg reagent. One key observation from the thermal desorption study ofsolid explosives residues is that the thermal dependence of the signalvaries by compound, thus the reagent mechanism does not take place insolution-phase at room temperature. Instead, the signal enhancement isdependent on thermal phase change properties, such as melting point andvapor pressure, which affect the mixing efficiency of available reagentwith the explosive.

FIGS. 6 and 7 show the desorption-temperature-dependence of the MSinstrument response from solid KClO₄ residue in the absence and presenceof the crown ether reagent. Signal continues to increase for KClO₄ withreagent at higher temperature (300° C.) as shown in FIG. 6; however, atthe expense of increasing background clutter due to chemical off-gassingfrom the unpassivated aluminum ionization source. Neat KClO₄ did notproduce a signal-to-background ration over 2, while in the presence ofcrown ether reagent, KClO₄ was detected at modest thermal desorptiontemperatures (200-250° C.) with a signal-to-background ratio of up to 5.Given this information, 200-250° C. is the most beneficial and practicaloperating temperature range for this analyte. The background will dependon instrument/source conditions, materials, and historical contaminationof the instrument. The 1:2 explosive-reagent mixture is reagent-limitedconditions. Greater signal enhancements are possible using even higheramounts of reagent molar excess.

EXAMPLE 3

FIGS. 8-10 show the desorption-temperature-dependent relationships ofthe MS instrument response from solid NaClO₄ residue in the absence andpresence of the crown ether reagent.

FIGS. 9 and 10 show TD-APCI-MS/MS instrument response versus thermaldesorption temperature for sodium perchlorate (NaClO₄) with and withoutdibenzo-21-crown-7 (DB21C7) reagent rendered as bothbackground-subtracted signal intensity (FIG. 9) and signal-to-backgroundratio (FIG. 10) determined using data in FIG. 8, comparing 5 μg NaClO₄(blue diamonds) and 5 μg NaClO₄ with 10 μg dibenzo-21-crown-7 (DB21C7)(red squares), where background is a clean silicon water substrate.

Signal continues to increase for NaClO₄ with reagent at highertemperature (300° C.) as shown in the FIG. 10; however, at the expenseof increasing background clutter from chemical off-gassing from theunpassivated aluminum ionization source. Neat NaClO₄ did not produce asignal-to-background ratio over 2, while in the presence of crown etherreagent, NaClO₄ was detected at modest thermal desorption temperatures(200-250° C.) with a signal-to-background ratio over 10. Given thisinformation, 250° C. is the most beneficial and practical operatingtemperature range for this analyte. The background will depend oninstrument/source conditions, materials, and historical contamination.The 1:2 explosive-reagent mixture is reagent-limited by molarity andsignal enhancement is expected to be considerably higher underexplosive-limited conditions, as shown in FIG. 8. Greater signalenhancements are possible using even higher amounts of reagent molarexcess.

EXAMPLE 4

Swipe substrates with reagents according to the invention impregnatedinto them were also developed. Through co-vaporization of both thetarget analyte and the reagent into the ionization space of aninstrument, the two become in communication with one another resultingin ionization of the target analyte. The ionization can result in theformation of a complex between the target analyte and the reagent withunique characteristics for detection. The complex can have detectableproperties that include shifts in mass or ion mobility for increasedselectivity. Also, if the target analyte was previously undetectable,formation of a complex can allow detection. In some cases, the complexwill be detectable with lower background and therefore increasesensitivity.

FIG. 11 illustrates the concept of doping a chemical reagent orionization reagent into a substrate material or swipe (usually made of afabric of polyester, muslin, or cotton). The substrate will entrain lowvolatility compounds until released by desorption (e.g. thermal). FIG.11 also provides a flow diagram comparison of the proposed ionizationreagent impregnated swipe approach versus the use of current swipes nochemical modification. The example shown is for chemical sensors withsample introduction via thermal desorption and detection of the ionizedreagent+target analyte adduct in either positive or negative ion mode.

The chemicals used in conventional ambient ionization sources areintroduced within the detection system as a vapor reagent in the carriergas. This limits the list of reagents to high vapor pressure and/orlower molecular weight candidates. Low volatility compounds oftenprovide higher affinity to the desired target analyte and increaseprobability of detection not achieved with higher volatility reagents.In addition, reagents can be used that are not otherwise amenable toentrainment in a carrier gas, thus making accessible a wider range ofionization reagents, including those of high molecular weight. Oneadvantage of high molecular weight (>400 Da) reagents is that can possesmore complex molecular structures and thus they can act as betterionization (or associative, evaporative, adductive or redox) reagents.These high molecular weight reagents are solids at room temperature andcannot be easily or reliably delivered as a vapor in a carrier gas.However, by virtue of their high molecular weight, they can formhigh-molecular adducts or complexes with the target analyte makingdetection much easier.

Ammonium nitrate residues were detected via API mass spectrometry usingregent-impregnated swipes. Ammonium (NH₄ ⁺) was present at m/z 18,however, this was below the low mass cutoff of many mass spectrometers.In order to detect ionized NH₄ ⁺ liberated by thermal desorption, aconventional thermal desorption swipe was chemically-modified toincorporate a crown ether reagent known to adduct NH₄ ⁺. The ionizationreagent yielded a higher molecular weight complex that was ionizable viaatmospheric-pressure chemical ionization.

In these experiments, a solid reagent, either dibenzo-21-crown-7(CAS#14098-41-0) or 18-crown-16 (CAS#17455-13-9), was entrained into thefabric of either muslin, cotton or polyester swipes. This swipe dopingprocedure consisted of drop-casting a known volume of a concentratedcrown ether stock solution in acetonitrile onto the swipe material. Thevolatile solvent was allowed to dry at room temperature leaving the lowvapor pressure crown ether in solid-state within the swipe matrix. Thereagent-impregnated swipe was then used to swipe a known mass of solidammonium nitrate residue from a Teflon surface. The contaminated swipewas placed on a thermal desorption stage which was pre-heated to 200° C.Ambient ionization mass spectrometry (specifically the Direct Analysisin Real Time® ionization source (JEOL/Ionsense) coupled with a 4000QTrapMS (ABSCIEX) operating in positive polarity was used to ionize thedesorbed product and detect the ionized crown ether reagent+NH₄ ⁻complex. This experiment was performed in open atmosphere whichcontained levels of ambient ammonia and produced NH₄ ⁻ upon positiveionization. Given the crown ether's high affinity for NH₄ ⁻, ambientammonia contributed to an elevate background in the mass channel for thereagent+NH₄ ⁺.

In these experiments, isotopically-labeled ¹⁵NH₄ ¹⁵NO₃ which shifts thereagents+¹⁵NH₄ ⁺ complex (M+19) to one higher mass unit than the productcreated by reagent+ambient NH₄ ⁺ (M+18) was utilized. Nitrogen gas wasused to purged or displace the air, however, the experiment was notperformed in a hermetically sealed chamber.

FIG. 12 is an overlay of two positive-mode mass spectra showingdetection of ammonium nitrate residue thermally-desorbed from thepolyester swipe impregnated with dibenzo-21-crown-7 reagent M. Withoutthe impregnated swipe (lower line), a conventional swipe would notprovide detection of ammonium above the low mass cutoff of many massspectrometer systems. With the impregnated swipe (upper line), a swipemodified with an ionization reagent provides detection of ammoniumindicating presence of the explosive. The single quadrupole massspectrum scan shows detection of the reagent+¹⁵NH₄ ⁺ adducts at m/z 828(2M+¹⁵NH₄ ⁺) and m/z 423 (M+¹⁵NH₄ ⁺). Free protonated reagent resides atm/z 405.6 (monomer) and 809.5 (dimer). Although the x axis(mass-to-change) was magnified to visualize the higher mass region, theconventional swipe is devoid of ammonium-related peaks above the lowmass threshold (˜m/z 45) of this instrument. Peak intensities in thepresence of ammonium residue versus a control swipe (reagent impregnatedswipe without ¹⁵NH₄ ⁺) at m/z 423 was S/N>3 and at m/z 828 was S/N>500.The same experiments with 18-crown-6 and ¹⁵NH₄ ¹⁵NO₃ were performed andproduced similar data with reagent+¹⁵NH₄ ⁺ adducts detected at m/z 547(2M+¹⁵NH₄ ⁺) and m/z 283 (M+¹⁵NH₄ ⁺).

EXAMPLE 5

FIG. 13 illustrates a number of general classes of reducing agents foruse as oxidizer ionization reagents. The chemical reaction between thereducing agent and the oxidizer are called reduction-oxidation (redox)reactions. In these reactions, the reduction potential, or potential togain electrons, is higher for the reducing agent than the analyte, thusthe final product is the reducing agent with additional oxygen atom(s).These classes of reagents include: 1) phosphines; 2) phosphites; 3)sulfides and sulfoxides; 4) aldehydes; 5) dienes; 6) amines; 7)heterocycles. Specifically, this reagent list includes but is notlimited to trimethylphosphine, triphenylphosphine, trimethylphosphite,trimethylphosphite, thiophene, thiophene-1-oxide, dimethylsulfoxide,sulfoxide, vanillin, butadiene, and ethanolamine. Each R group in FIG.13 is an atom or side chain selected independently from the groupsincluding but not limited to hydrogen, straight or branched chain alkyl,straight or branched chain alkenyl, aryl, heteroaryl, heterocycle, andcarbocycle.

The reducing agents, or reactive ionization reagents, produce anindirect technique for detecting oxidizers. For example, the reaction ofhydrogen peroxide (H₂O₂) with 4-nitrophenyl boronic acid to form the newchemical product, 4-nitrophenol, provides a means of indirect detectionof the peroxide. The data below is a demonstration of utilizing such areagent in hydrogen peroxide detection via APCI-MS. The reaction ofhydrogen peroxide with 4-nitrophenylboronic acid is simple way tomeasure concentration of hydrogen peroxide as it stoichiometricallyconverts 4-nitrophenylboronic acid into 4-nitrophenol, as shown below.

We adapted this reaction for APCI-MS and MS/MS to indirectly detecthydrogen peroxide using 4-nitrophenylboronic acid as a reactive reagent.The sensitivity of this technique will be limited by the backgroundsignal of the oxidation product. The 4-nitrophenol oxidation product(m/z 138) was observed in the MS scan of the reagent itself,4-nitrophenylboronic acid, and may result from two potential sources.The reagent may oxidize during manufacturing, storage, or during APCI inwhich O₂ ⁻ species are present. This indirect means of detection isattractive given the low mass of hydrogen peroxide and its highlyreactive nature. Practical field use of reactive reagents with highoxidation potential is expected to be limited given their tendency tooxidize through the fundamental APCI mechanism.

FIG. 14 shows the negative-mode single quadrupole scan of 100 μM4-nitrophenylboronic acid overlaid with 100 μM 4-nitrophenylboronic acidwith 37 μM hydrogen peroxide (1.25%) prepared in 50/50 methanol-water.Deprotonated 4-nitrophenylboronic acid at m/z of 166 and thedeprotonated 4-nitrophenol peak at m/z 138 are observed.

Upon addition of hydrogen peroxide, the 4-nitrophenylboronic acid signalclearly decreased while that of the oxidation product, 4-nitrophenyl,increased. To confirm these observations, we analyzed samples containing100 μM 4-nitrophenylboronic acid in 50/50 methanol-water with variedconcentration of hydrogen peroxide. Concentration of hydrogen peroxidewas varied from 0.1 to 7353 μM (0.00025-25%). Blanks consisted of 100 μM4-nitrophenylboronic acid. Samples were analyzed by direct infusionnegative mode APCI. MS/MS transitions were monitored for both4-nitrophenylboronic acid via m/z 166→46 (C₆H₅BNO₄ ⁻ to NO₂ ⁻) and4-nitrophenyl via m/z 138→92 (C₆H₄NO₃ ⁻ to C₆H₄O⁻).

To evaluate the practical application for indirect detection of hydrogenperoxide as an oxidation product of 4-nitrophenylboronic acid, wecalculated a signal-to-background ratio for the peak areas of the samplecontaining hydrogen peroxide to the blank containing only 100 μM4-nitrophenylboronic acid. Results of the MS/MS analysis are presentedin FIG. 15. Monitoring the signal increase resulting from 4-nitrophenylproduced by hydrogen peroxide oxidation of 4-nitrophenylboronic acid canprovide a mechanism for detection of hydrogen peroxide over wide rangeof H₂O₂ concentrations (0.0025-25% v/v). Selectivity of this detectioncan be improved by monitoring two detection channels in MS/MS modeincluding signal decrease from consumption of the 4-nitrophenylboronicacid reagent and signal increase for generation of 4-nitrophenol.

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. All patents,publications and references cited herein (including the following listedreferences) are expressly incorporated herein by reference in theirentirety.

What is claimed is: 1-20. (canceled)
 21. Apparatus for directlydetecting a target analyte, M, potentially present in a sample as anionizable compound or complex, MX, capable of dissociating intoconstituent ionic species, M⁻ and counter-ions X⁺,the apparatuscomprising a container or swipe for introducing a reagent into a massspectrometer and a reagent within the container or associated with theswipe, the reagent comprising an associative reagent, A, formulated tosequester at least one ionic component, X⁺, of the analyte as a compoundor complex XA, thereby ensuring greater availability of the ionizedanalyte, M⁻, for detection.
 22. The apparatus of claim 21, wherein thereagent comprises at least one of β-keto esters, crown ethers, glymes,sugars, cryptands, ionic dyes, and cavitands.
 23. The apparatus of claim21, wherein the reagent comprises a crown ether selected from the groupof 12-crown-4, 15-crown-5, 16-crown-4, dibenzo 21-crown-7 and18-crown-6.
 24. The apparatus of claim 21, wherein the reagent comprisesa dibenzo-21-crown-7 ether (CAS#14098-41-0).
 25. The apparatus of claim21, wherein the reagent comprises a cryptand selected from the group of1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8] hexacosane andkryptofix
 222. 26. The apparatus of claim 21, wherein the reagentcomprises a cavitand selected from the group of cyclodextrin,calixarene, pillararene and cucurbituril.
 27. The apparatus of claim 21,wherein the reagent comprises a sugar selected from the group ofsucrose, fructose and glucose.
 28. The apparatus of claim 21, whereinthe reagent comprises dimethoxyethane.
 29. The apparatus of claim 21,wherein the apparatus further comprises a second reagent within thecontainer or associated with the swipe to form an acid analog of theanalyte by proton donation.
 30. The apparatus of claim 29, the secondreagent comprises at least one reagent selected from the group ofsulfuric acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid,hydrobromic acid, nitric acid, oxalic acid, water, hydrogen sulfate,phosphoric acid, formic acid, benzoic acid, acetic acid, propionic acid,or other organic acids of the form R—COOH where R is an alkyl,substituted alkyl, aryl, or substituted aryl group, or an alkyl ammoniumcompound. 31-36. (canceled)
 37. Apparatus for detecting a target analytecomprising a container or swipe for introducing a reagent into a massspectrometer and an evaporative reagent within the container orassociated with the swipe to form a higher vapor pressure analog of theanalyte.
 38. The apparatus of claim 37 wherein the evaporative reagentis an acid reagent to form a conjugate acid of the analyte if present inthe sample.
 39. The apparatus of claim 37 wherein the evaporativereagent is disposed in a container adapted for coupling with the massspectrometer for introduction of the evaporative regent via a carriergas.
 40. The apparatus of claim 37 wherein the evaporative reagent iseither physically entrained in a swipe, bound to the swipe vianon-covalent chemical bonds, or bound to the swipe via thermally labilecovalent bonds.
 41. The apparatus of claim 37, the evaporative reagentcomprises at least one acid reagent selected from the group of sulfuricacid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, hydrobromicacid, nitric acid, oxalic acid, water, hydrogen sulfate, phosphoricacid, formic acid, benzoic acid, acetic acid, propionic acid, or otherorganic acids of the form R-COOH where R is an alkyl, substituted alkyl,aryl, or substituted aryl group.
 42. The apparatus of claim 37 whereinthe evaporative reagent comprises a quaternary ammonium cation donorselected from the group of quaternary ammonium salts that can donate acation having the formula, N-R1-R2-R3-R4, where R1, R2, R3 and R4 arehydrogen or straight or branched alkyl, preferably lower alkyl, groups.43. The apparatus of claim 37 wherein the apparatus further comprises anassociative reagent within the container or associated with the swipefor sequestering a counter-ion of the analyte. 44-51. (canceled) 52.Apparatus for detecting a target analyte comprising a container or swipefor introducing a reagent into a mass spectrometer and reducing reagentselected from the group of phosphines; phosphites; sulfides andsulfoxides; aldehydes; dienes; amines and heterocycles.
 53. Theapparatus of claim 52, wherein the reducing reagent comprises at leastone reagent selected from the group of trimethylphosphine,triphenylphosphine, trimethylphosphite, trimethylphosphite, thiophene,thiophene-1-oxide, dimethylsulfoxide, sulfoxide, vanillin, butadiene,and ethanolamine.
 54. The apparatus of claim 52 wherein the container isadapted for coupling with a mass spectrometer for introduction of thereducing regent via a carrier gas.